The PKB (protein kinase B, also called Akt) family of protein kinases plays a key role in insulin signaling, cellular survival, and transformation. PKB is activated by phosphorylation on residues threonine 308, by the protein kinase PDK1, and Serine 473, by a putative serine 473 kinase. Several protein binding partners for PKB have been identified. Here, we describe a protein partner for PKBalpha termed CTMP, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of PKBalpha at the plasma membrane. Binding of CTMP reduces the activity of PKBalpha by inhibiting phosphorylation on serine 473 and threonine 308. Moreover, CTMP expression reverts the phenotype of v-Akt-transformed cells examined under a number of criteria including cell morphology, growth rate, and in vivo tumorigenesis. These findings identify CTMP as a negative regulatory component of the pathway controlling PKB activity.

In the ITT analysis, no significant difference in PFS was observed between treatment arms based on CRR. In the post hoc subset analyses, nilotinib provided significantly longer median OS.

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In this study, we have identified novel regulatory steps involved in the cross-talk between protein kinase B (PKB) and MAPK signaling pathways. We found that PKB down-regulates the Ras-Raf-MEK-ERK pathway by reducing the activity of ERK, which leads to inactivation of the transcription factor Elk1. In addition, PKB is able to reduce protein levels of Elk1. Both events lead to suppression of serum response element (SRE)-dependent transcription and a consequent decrease in the transcription of SRE-containing genes, such as c-fos. Because activation of the Ras/MAPK cascade is reported to increase c-fos transcription before apoptosis, our results are consistent with a specific role for PKB in promoting cell survival. Decrease in c-Fos protein levels in glioblastoma cells with constitutively active PKB provides further support for our observations. Therefore, our findings delineate a novel mechanism regulating immediate-early transcription, which may be involved in the initial steps in PKB-induced oncogenic transformation.

Nilotinib, a potent orally bioavailable BCR-ABL tyrosine kinase inhibitor, is currently available as a hard gelatin capsule that must be swallowed whole. For patients who may have difficulty swallowing the intact capsule, an alternative mode of administration is desirable. The authors compared the bioavailability of nilotinib from the following administrations in 48 healthy subjects: (1) 400 mg nilotinib given as two 200-mg nilotinib intact capsules; (2) contents of two 200-mg nilotinib capsules, each capsule dispersed in 1 teaspoon of nonfat plain yogurt; and (3) contents of two 200-mg nilotinib capsules, each capsule dispersed in 1 teaspoon of applesauce. Nilotinib absorption was modestly increased following the administration of nilotinib dispersed in yogurt. The geometric mean ratios (90% confidence intervals) for nilotinib C(max), AUC(0-tlast), and AUC(0-inf) were 1.31 (1.22-1.41), 1.11 (1.05-1.16), and 1.08 (1.02-1.15), respectively. Administration of nilotinib dispersed in applesauce showed equivalent bioavailability compared with administration of nilotinib as intact capsules. The geometric mean ratios (90% confidence intervals) for nilotinib C(max), AUC(0-tlast), and AUC(0-inf) were 0.95 (0.88-1.02), 0.99 (0.94-1.04), and 0.97 (0.90-1.03), respectively. Each treatment was well tolerated in the study subjects. The data support a feasible alternative method of nilotinib administration; each capsule's contents may be dispersed in 1 teaspoon of applesauce and taken immediately.